Direct observation of enantiomer discrimination of epoxides by chiral salen complexes using ENDOR

Electron nuclear double resonance (ENDOR) spectroscopy was used to investigate the weak enantioselective binding between chiral salen complexes [VO(1)] ((R,R)- and (S,S)-vanadyl N,N'-bis(3,5-di-tert-butylsalcylidene)-1,2-cyclohexanediamine) and chiral epoxides (e.g., (R)-/(S)-propylene epoxide, 5) in frozen (10 K) solution. Differences in epoxide binding by enatiomers of [VO(1)] was evidenced by changes to the 1H epoxide derived peaks in the ENDOR spectra, such that (R,R)-[VO(1)] + (R)-5 and (R,R)-[VO(1)] + (S)-5 yield noticeably different spectra. These changes were assigned to the small structural differences between the diastereomeric metal-epoxide adducts. Simulation of the spectra revealed differences in the VO...1Hepoxide distances for the diastereomeric pairs, which was confirmed by a complementary set of density functional theory (DFT) calculations. While the epoxide molecule is very weakly coordinated, ENDOR measurements of the racemic complex in racemic epoxide nevertheless indicated the preferential coordination of the (R)-5 to (R,R)-[VO(1)] (likewise (S)-(5) to (S,S)-[VO(1)]), which is favored over the binding of (S)-5 epoxide to (R,R)-[VO(1)] (and likewise (R)-5 epoxide to (S,S)-[VO(1)]). This demonstrates the unique power of the ENDOR technique to resolve weak chiral interactions for which EPR spectroscopy alone lacks sufficient resolution.     

Epoxide hydrolase-catalyzed enantioselective synthesis of chiral 1,2-diols via desymmetrization of meso-epoxides. lzhao@diversa.com

The discovery, from nature, of a diverse set of microbial epoxide hydrolases is reported. The utility of a library of epoxide hydrolases in the synthesis of chiral 1,2-diols via desymmetrization of a wide range of meso-epoxides, including cyclic as well as acyclic alkyl- and aryl-substituted substrates, is demonstrated. The chiral (R,R)-diols were furnished with high ee's and yields. The discovery of the first microbial epoxide hydrolases providing access to complementary (S,S)-diols is also described.     

Chiral lithium amide base-mediated rearrangement of meso-cyclohexene oxides: asymmetric synthesis of amino- and aziridinocyclohexenols

Two different chiral lithium amide base routes for the synthesis of amino- and aziridino-containing cyclohexenols have been explored. The first strategy involved the diastereoselective preparation of novel meso-aziridinocyclohexene oxides and their subsequent enantioselective rearrangement using chiral bases. In this approach, the diphenylphosphinoyl nitrogen protecting group proved optimal and aziridinocyclohexenols of 47-68% ee were obtained. Of particular note was the smooth rearrangement of the epoxide to an allylic alcohol in the presence of an aziridine: under optimised chiral base conditions, the aziridine remained essentially unaffected. A second more straightforward strategy for introduction of an amino functionality was also investigated: (1S,4R,5S)- and (1R,4R,5S)-4,5-bis(tert-butyldimethylsilyloxy)cyclohex-2-enols, readily prepared in > 95% ee using a chiral base approach, were subjected to Mitsunobu substitution using a sulfonamide and Overman rearrangement.     

Exploring chemical diversity of epoxyquinoid natural products: synthesis and biological activity of (-)-jesterone and related molecules

Enantioselective syntheses of the potent antifungal agent (-)-jesterone, its hydroxy epimer, and a dimeric quinone epoxide derivative are reported. The synthesis involves diastereoselective epoxidation of a chiral quinone monoketal derivative and regio- and stereoselective reduction of a quinone epoxide intermediate.     

Synthesis of potent and orally efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016

Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11β-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11β-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.     

Enantioselective trans dihydroxylation of nonactivated C-C double bonds of aliphatic heterocycles with Sphingomonas sp. HXN-200

The bacterial strain Sphingomonas sp. HXN-200 was used to catalyze the trans dihydroxylation ofN-substituted 1,2,5,6-tetrahydropyridines 1 and 3-pyrrolines 4 giving the corresponding 3,4-dihydroxypiperidines 3 and 3,4-dihydroxypyrrolidines 6, respectively, with high enantioselectivity and high activity. The trans dihydroxylation was sequentially catalyzed by a monooxygenase and an epoxide hydrolase in the strain with epoxide as intermediate. While both epoxidation and hydrolysis steps contributed to the overall enantioselectivity in trans dihydroxylation of 1, the enantioselectivity in trans dihydroxylation of the symmetric substrate 4 was generated only in the hydrolysis of meso-epoxide 5. The absolute configuration for the bioproducts (+)-3 and (+)-6 was established as (3R,4R) by chemical correlations. Preparative trans dihydroxylation of 1a and 4b with frozen/thawed cells of Sphingomonas sp. HXN-200 afforded the corresponding (+)-(3R,4R)-3,4-dihydroxypiperidine 3a and (+)-(3R,4R)-3,4-dihydroxy pyrrolidine 6b in 96% ee both and in 60% and 80% yield, respectively. These results represent first examples of enantioselective trans dihydroxylation with nonterpene substrates and with bacterial catalyst, thus significantly extending this methodology in practical synthesis of valuable and useful trans diols. Enantioselective hydrolysis of racemic epoxide 2a with Sphingomonas sp. HXN-200 gave 34% of (-)-2a in >99% ee, which is a versatile chiral building block. Further hydrolysis of (-)-2a with the same strain afforded (-)-(3S,4S)-3a in 96% ee and 92% yield. Thus, both enantiomers of 3a can be prepared by biotransformation with Sphingomonas sp. HXN-200.     

Efficient preparation of highly optically active (S)-(-)-2,3-allenols and (R)-(+)-2,3-allenyl acetates by a clean novozym-435-catalyzed enzymatic separation of racemic 2,3-allenols

Novozym-435 has been found to be an effective biocatalyst for the kinetic resolution of a series of racemic 2,3-allenols, affording highly optically active (S)-(-)-2,3-allenols and (R)-(+)-2,3-allenyl acetates in high yields and with excellent ee values. The reaction of 3-(n-butyl)-3,4-pentadien-2-ol (1 a) was successfully performed on a 10 g scale to afford the corresponding (S)-(-)-2,3-allenol (1 a) and (R)-(+)-2,3-allenyl acetate (2 a) in synthetically useful amounts and with high ee values. The advantages of this reaction are the ready availability of the starting materials, high stereoselectivities for both (-)-2,3-allenols and (+)-2,3-allenyl acetates, the use of a relatively high substrate concentration, and a lower catalyst loading. The resulting (S)-(-)-2,3-allenol 1 a can be converted into the corresponding chiral 2,5-dihydrofuran and the vinylic epoxide.     

Stereoselective 4-benzyloxybut-2-enylation of aldehydes via an allyl-transfer reaction using a chiral allyl donor

[reaction: see text] A direct and highly stereoselective (E)-4-benzyloxybut-2-enylation of aldehydes was successfully carried out to give 5-benzyloxyhomoallylic alcohol (11) via an allyl-transfer reaction using a chiral allyl donor (10). The chiral allyl donor (10) was prepared by catalytic Sharpless asymmetric epoxidation of 3-methylbut-2-en-1-ol, followed by a stereospecific vinyl Grignard reaction of the epoxide in the presence of CuBr and selective benzylation of the primary alcohol of diol.     

用(R)-(+)-缩水甘油的亲核开环反应制备手性连二醇

以D-甘露醇为原料合成(R)-(+)-缩水甘油1。该环氧化合物的亲核开环反应为高立体选择性地(93%-96%e.e.)制备各种手性连二醇提供了一条简便途径。     

CEC enantioseparations on chiral monolithic columns: a study of the stereoselective degradation of (R/S)-dichlorprop [2-(2,4-dichlorophenoxy)propionic acid] in soil

For the study of the stereoselective degradation of the herbicide 2-aryloxipropionic acid dichlorprop (DCPP) in soil, a porous monolithic chiral column (100 microm id) was prepared by in situ copolymerization of glycidyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate in the presence of formamide and 1-propanol as the porogen solvents. Subsequently, the epoxide groups at the surface of the monolith were reacted with (+)-1-(4-aminobutyl)-(5R,8S,10R)-terguride as the chiral selector. Optimum conditions for the herbicide resolution by CEC were found using mobile phases consisting of acetic acid/triethylamine mixtures in ACN-methanol (9:1 v/v). Under these conditions fully separation of DCPP enantiomers in the presence of clofibric acid (internal standard) was achieved in about 5 min. Experiments on the incubation of rac-DCPP in soil at room temperature showed the herbicide undergone during 23 incubation days to a degradation to levels 相似文献   

大位阻烯烃不对称环氧化合成手性环氧化合物

采用大位阻的有机锂试剂或格氏试剂与卤代烯烃偶联合成了7种大位阻取代烯烃. 以Oxone(KHSO₅)作为氧化剂, 分别在D-果糖衍生酮和(2S,5R)-2-异丙基-5-甲基环己酮为催化剂的催化下, 将合成的7种大位阻取代烯烃转变成了7个大位阻的手性环氧化合物. 其中以D-果糖衍生酮的对映选择性最好, 当双键碳上含有3个取代基时, 对映选择性最高, e.e.值为96.8%~99.5%. (2S, 5R)-2-异丙基-5-甲基环己酮的对映选择性较差, 无论是一取代的烯烃还是三取代的烯烃, 其e.e.值均介于25.6%~34.1%之间.     

Enantioselective synthesis of fatty acid amide hydrolase inhibitors with 1,3-disubstituted butan-2-one scaffold

Fatty acid amide hydrolase is a key enzyme in the inactivation of the analgesic and anti-inflammatory endocannabinoid anandamide. Previously, the chiral compound 1-(1H-benzotriazol-1-yl)-3-(4-phenylphenoxy)butan-2-one was identified as a potent inhibitor of fatty acid amide hydrolase and is therefore of interest as a potential agent against pain and inflammation. Two different approaches for the enantioselective synthesis of fatty acid amide hydrolase inhibitors with a 1,3-disubstituted butan-2-one scaffold were carried out. The first one uses the chiral epoxide 2-[1-(4-phenylphenoxy)ethyl]oxirane with an (R)- or (S)-configuration at the exocyclic stereocenter as central intermediates. These substances were obtained by separation of the non-stereoselectively synthesized epoxide into its racemic diastereomers by reversed phase chromatography followed by Jacobsen’s hydrolytic kinetic resolution of each enantiomer with the (S)-configured oxirane ring. Furthermore, a chiral pool based enantioselective synthesis was developed. In that case, the starting compound for both target enantiomers was methyl 3,4-O-isopropylidene-l-threonate. In comparison to the first approach, the chiral pool synthesis consisted of more steps, but generated the enantiomers with much better enantiomeric excess. Biological evaluation showed that the (R)-enantiomer inhibits isolated fatty acid amide hydrolase with a 200-fold higher activity than the (S)-enantiomer.     

Synthesis of 4,6-dideoxyfuranoses through the regioselective and diastereoselective oxyfunctionalization of a dimethylphenylsilyl-substituted chiral homoallylic alcohol.

The 4,6-dideoxyfuranoses 10a and 10b have been synthesized by starting from the readily available E-5-dimethylphenylsilyl-2-hexene-4-ol (1) and employing successively three versatile oxyfunctionalization methods, namely photooxygenation, metal-catalyzed epoxidation, and oxidative desilylation. Photooxygenation of the hydroxy vinylsilane 1 and subsequent triphenylphosphine reduction of the hydroperoxides 3 afford the like-4a and unlike-4b diols, which have been converted separately to the tetrahydrofurans (2S*,3R*,5R*)-7a and (2S*,3R*,5S*)-7b by a combination of diastereoselective epoxidation and regioselective intramolecular epoxide-ring opening. In the epoxidation reaction, catalyzed by Ti(OiPr)(4) or VO(acac)(2), only one diastereomer (dr >95:5) of the epoxide 5 is obtained. Further intramolecular opening of the epoxide ring in erythro-5 occurs regioselectively at the C-alpha position and diastereoselectively under inversion of the configuration of the silyl-substituted stereogenic center to generate only one diastereomer of the tetrasubstituted tetrahydrofurans 7. Oxidative desilylation of the latter gave the hitherto unknown 4,6-dideoxyfuranoses 10a and 10b. The use of the optically active E-5-dimethylphenylsilyl-2-hexene-4-ol (1) as starting material, which is readily available through lipase-catalyzed kinetic resolution, leads to the D- and L-4,6-dideoxysorbofuranoses 10a and D- and L-4,6-dideoxyfructofuranoses 10b in up to 98% enantiomeric excess.     

Total synthesis of the microtubule-stabilizing agent (-)-laulimalide

[structure: see text] The total synthesis of the potent microtubule-stabilizing anticancer agent (-)-laulimalide has been achieved in 27 steps and 2.9% overall yield. Notable features are the use of Jacobsen HDA chemistry for the enantioselective construction of the side chain dihydropyran, a diastereoselective aldol coupling using chiral boron enolate methodology, a Mitsunobu macrolactonization, and a Sharpless AE to introduce the epoxide onto des-epoxy-laulimalide.     

Beckmann裂解反应在天然产物Fumagillin和Ovalicin前体及衍生物全合成中的应用

以Hajos酮为原料,经环氧化、酸催化开环、烷基化(或酰基化)仲羟基、一步立体选择性氢化/缩酮保护等反应,方便地在双环适当的位置引入烷氧基,再应用PCl5/2,6-二甲基吡啶/CH2Cl2进行Beckmann裂解反应,将五员环开环生成相应的烯-腈化合物,高收率地合成了Fumagillin和Ovalicin前体及衍生物3-[1-烷氧基-5,5-(1,2-亚乙二氧基-5-甲烯基)环己基丙腈(7a~7d)和2-甲氧基-3-丙腈-4-甲烯基环己酮(8a),并构建其重要的手性环状骨架。化合物的的结构经NMR,IR和MS确证,其中8a为未见文献报道的新化合物。     

Synthesis, reactivity and complexation studies of N,S exo-heterodisubstituted o-carborane ligands. Carborane as a platform to produce the uncommon bidentate chelating (pyridine)N-C-C-C-s(H) motif

The synthesis of N,S-heterodisubstituted 1-(2'-pyridyl)-2-SR-1,2-closo-C2B10H10 compounds (R = Et, 2; R = (i)Pr, 3) has been accomplished starting from 1-(2'-pyridyl)-l,2-closo-C2B10H11 (1), and their partial deboronation reaction leading to the structurally chiral [7-(2'-pyridyl)-8-SR-7,8-nido-C2B9H10]-derivatives (R = Et, [4]-; R = (i)Pr, [5]-) has been studied. Capillary electrophoresis combined with the chiral selector alpha-cyclodextrin has permitted the separation of the electrophoretically pure racemic [7-(2'-pyridyl)-8-SR-7,8-nido-C2B9H11]- ions into two peaks each one corresponding to the interaction of one enantiomer with the alpha-cyclodextrin. The N,S-heterodisubstituted o-carborane containing a mercapto group, 1-(2'-pyridyl)-2-SH-1,2-closo-C2B10H10, 1, is one of the two examples of a rigid bidentate chelating (pyridine)N-C-C-C-S(H) motif having been structurally fully characterized. To study the potential of such a binding site, 1 has been tested as a ligand with metal ions requiring different coordination numbers, two (Au(+)) and four (Pd2+ and Rh+). The crystal structures of the Pd(II) and Au(I) complexes are reported. For the Pd(II) complex, 1 acts as a bidentate ligand whereas for Au(I), 1 acts as a monodentate ligand through the thiolate.     

Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular β-glucosidase 2, and other glycosidases

Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible male contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve ring-closing metathesis and Sharpless asymmetric dihydroxylation and for the four-membered analogues Sharpless epoxidation, epoxide ring-opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6) was moderately active against rat-derived ceramide-specific glucosyltransferase, and four of the other eight-membered analogues were weakly active against rat-derived β-glucosidase 2. Among the four-membered analogues, ((2R,3S,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25) displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat-derived enzyme. ((2S,4S)-3-Hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (27) was found to be a selective inhibitor of β-glucosidase 2, with potency similar to NB-DNJ. Additional glycosidase assays were performed to identify potential other therapeutic applications. The eight-membered iminosugars exhibited specificity for almond-derived β-glucosidase, and the 1-nonylazetidine 25 inhibited α-glucosidase (Saccharomyces cerevisiae) with an IC(50) of 600 nM and β-glucosidase (almond) with an IC(50) of 20 μM. Only N-nonyl derivatives were active, emphasizing the importance of a long lipophilic side chain for inhibitory activity of the analogues studied.     

The docking of chiral epoxides on the Whelk-O1 stationary phase: a molecular dynamics study

The docking of analytes on the Whelk-O1 chiral stationary phase is explored for two chiral epoxides in a hexane solvent. Density functional theory calculations are employed to develop flexible models for R/S-styrene oxide (phenyl oxirane) and (R,R/S,S)-stilbene oxide (2,3-diphenyl oxirane). Molecular dynamics simulations of the racemates in the presence of the Whelk-O1 chiral stationary phase reveal the distribution of the enantiomers at the interface. The importance of hydrogen bonding and ring-ring interactions is explored along with an examination of the major docking arrangements. The interactions between the Whelk-O1 molecules and the chiral epoxide enantiomers are quite distinct and consistent with the experimental elution orders [S.E. Schaus, B.D. Brandes, J.F. Larrow, M. Tokunage, K.B. Hansen, A.E. Gould, M.E. Furrow, E.N. Jacobsen, J. Am. Chem. Soc. 124 (2001) 1307] and separation factors [W.H. Pirkle, C.J. Welch, Tetrahedron: Asymm. 5 (1994) 777]. The impact of a polar solvent modifier is examined for R/S-styrene oxide where selectivity in 80:20 n-hexane:2-propanol is assessed.     

An Asymmetric Synthesis of L-694,458, a Human Leukocyte Elastase Inhibitor, via Novel Enzyme Resolution of beta-Lactam Esters

A convergent synthesis of [S-(R,S)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, was achieved via chiral synthesis of key intermediates: (S)-3,3-diethyl-4-[4'-[(N-methylpiperazin-1-yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl isocyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enantioselective lipase hydrolysis of ester 5 to produce (S)-3,3-diethyl-4-(4'-carboxyphenoxy)-2-azetidinone (6) (60% yield, three cycles, 93% ee) with isolation, epimerization, and recycling of the undesired (R)-ester 5. Isocyanate 3 was prepared by chiral addition of Zn(n-Pr)(2) to piperonal (98% yield, 99.2% ee), azide displacement and reduction to (R)-alpha-propylpiperonylamine (11) (58% yield, 85% ee), crystallization as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanate formation (98% yield) with phosgene.     

Stereoselective determination of R(-)- and S(+)-MK-571, a leukotriene D4 antagonist, in human plasma by chiral high-performance liquid chromatography.

A stereoselective high-performance liquid chromatographic method that utilizes fluorescence detection was developed for the selective and sensitive quantification of R(-)- and S(+)-enantiomers of MK-571 (1), a potent and specific leukotriene D4 antagonist, in human plasma. Racemic 1 was isolated from the acidified plasma using solid-phase extraction and the resulting residue was successfully reacted with isobutyl chloroformate and R(+)-1-(1-naphthyl)ethylamine in triethylamine-acetonitrile medium to form the diastereomer of each enantiomer. A structural analogue of 1 was used as internal standard. The derivatized sample was dissolved in 1,1,2-trichlorotrifluoroethane and an aliquot was chromatographed on a (R)-urea chiral column using a mobile phase containing 89% triethylamine-pentane (3:1000, v/v), 10% 2-propanol, and 1% acetonitrile at a flow-rate of 1.5 ml/min. The fluorescence response (excitation wavelength, 350 nm; emission wavelength, 410 nm) was linear (r2 greater than 0.999) for concentrations of enantiomers of 1 from 0.05 micrograms/ml, the lowest quantitation limit, up to 2.5 micrograms/ml. Intra-day coefficients of variation at 0.05 microgram/ml were 2.4% for the R(-)-isomer and 2.0% for S(+)-isomer. The corresponding inter-day coefficients of variation for R(-)- and S(+)-1 were 2.6 and 3.6%, respectively. The utility of the methodology was established by analysis of plasma samples from male volunteers receiving single intravenous and oral doses of racemic 1.